Use of unsymmetrical esters of n-substituted 1,4-dihydropyridine 3,5-dicarboxylic acid as cardio-vascular agents

ABSTRACT

Unsymmetrical esters of N-substituted 4-substituted-1,4dihydropyridine 3,5-dicarboxylic acid optionally substituted by lower alkyl groups in the 2- and 6-positions are cardio-vascular agents. The compounds, of which 1,2,6-trimethyl-4-(3&#39;&#39;nitrophenyl)-1,4-dihydropyridine 3,5-dicarboxylic acid 3-methyl5-ethyl ester is a typical example, can be prepared (A) through condensation of an ylidene- Beta -ketocarboxylic acid ester, with a Beta -ketocarboxylic acid ester and an amine or salt thereof, or with an enamino carboxylic acid ester or (B) through condensation of an aldehyde, an enamino carboxylic acid ester and a Beta -ketocarboxylic acid ester.

United States Patent [191 Meyer et al.

[451 Nov. 18, 1975 USE OF UNSYMMETRICAL ESTERS OF N-SUBSTITUTED1,4-DIHYDROPYRIDINE 3,5-DICARBOXYLIC ACID AS CARDIO-VASCULAR AGENTS [75]Inventors: Horst Meyer; Friedrich Bossert,

' both of Wuppertal-Elberfeld; Wulf Vater, Opladen; Kurt Stoepel,Wuppertal-Vohwinkel, all of Germany [73] Assignee: BayerAktiengesellschaft, Germany [22] Filed: May 30, 1974 [21] Appl. No.:474,407

Related US. Application Data [62] Division of Ser. No. 336,605, Feb. 28,1973, Pat. No.

[30] Foreign Application Priority Data Mar. 6, 1972 Germany 2210672 [52]US. Cl 424/266; 424/226 [51] Int. Cl? A61K 31/455; A61K 31/655 [58]Field of Search 424/226, 251, 263, 266

[56] I References Cited UNITED STATES PATENTS 3,799,936 3/1974 Meyer etal 260/2955 R Primary Examiner-Albert T. Meyers Assistant ExaminerDarenM. Stephens ABSTRACT 5 tl Claims, No Drawings This is a division ofapplication Ser. No. 336,605 filed Feb. 28, 1973 now U.S. Pat. No.3,883,540.

The present invention relates to certain new unsym- The term loweralkynyl denotes a univalent branched i or straight hydrocarbonchain-containing from 2 to 6 metrical N-substituted1,4-dihydropyridinedicarboxy- 1 lic acid esters, to processes for theirproduction, and to their use'as coronary and anti-hypertensive agents.

It has already been disclosed that N-alkyl l',4-dihydropyridines areobtained by reaction of l,5-diketones with alkylamines (Merz, Richter,Arch. Pharm. 275, 294 (1937). A known variant of this process consistsin the reaction of aldehydes with B-dicarbonyl compounds and aminehydrochlorides according to German Offenlegungschrift l,923,990.Symmetrical 1,4- dihydropyridine derivatives were produced by thesemethods. Until the present invention, it has not been possible toproduce unsymmetrical esters of the N-substituted l,4-dihydropyridinesand such esters have hitherto not been disclosed. 4

The present invention relates to unsymmetrical 1,4-

dihydropyridinecarboxylic acid esters of the general formula:

in which R is mono-, dior tri'substituted phenyl, in which thesubstituents are selected fromthe group consisting of nitro, cyano,azido and S(O),,-lower alkyl, wherein n O, l or 2, lower alkyl, loweralkoxy andhalogeno, the total number of said substituents being not morethan 3 and at least one of said substituents being nitro, cyano, azidoor S(O),,-lower alkyl; or R is an aromatic ring system selected from thegroup consisting of naphthyl, quinolyl and isoquinolyl; or R is aheterocyclic ring system selected from the group consisting of pyridyl,pyrimidyl, thenyl, furyl and pyrryl, said aromatic ring system and saidheterocyclic ring system being unsubstituted or substituted by. at leastone lower alkyl, lower alkoxy or halogeno;

R and R independent of the other, is hydrogen or lower alkyl;

R and R are different from one another and are lower alkyl, loweralkenyl, lower alkynyl, lower alkoxy(lower alkyl) or lower cycloalkyl,unsubstituted or substituted by hydroxy;

R is lower alkyl or benzyl.

The term lower alkyl denotes a univalent saturated branched or straighthydrocarbon chain containing from 1 to 6 carbon atoms as, for example,methyl and hexyl.

The term lower alkenyl denotes ajunivalent branched or straighthydrocarbon chain containing from 2 m6 carbon atoms and ,ethylenicunsaturation as, for example, vinyl and 4-hexenyl. i i

carbon atoms and acetylenicuns'aturation as, for example, ethynyl andS-heXyn yL The term lower alkoxy denotes a straight or branchedhydrocarbon 'chain bound to thei'mainder of the molecule th'roughariethereal oxygen atoin as, for example, methoxy and hexoxy.

The term halogeno denotes the substituents fluoro, chloro, bromo andiodo.

The term lower cycloalkyl denotes a univalent cyclic hydrocarbon ringhaving 3 to 6 carbon atoms, as for exout limitation, hydrochloric acid,hydrobromic acid,

phosphoric acid, sulfuric acid, methane sulphonic acid, acetic acid,tartaric acid, lactic acid, succinic acid, citric acid, malic acid,maleic acid, sorbic acid, aconitic acid, salicyclic acid, phthalicacid,=embonic acid, enanthic acid, and the like. I

The compounds of the present invention can exist as optical isomers andboth the racemates of these isomers and the individual isomersthemselves are within the scope of the present invention. The racematescan be separated into their individual isomers through thewell-known-technique and forming diastereoisomeric salts with opticallyactive acids.

In the general formula I, above, the present invention may be moreparticularly defined'as follows:

R is phenyl radical substituted by l or 2 nitro, especially one nitro,or by one cyano, azido or S(O),,-lower alkyl, where n is O or 2,particularly of 1 to 4 carbon atoms, and which may also be substitutedby lower alkyl or lower alkoxy, particularly of l to 4 carbon atoms andalkyl or lower alkoxy, particularly of l to 4 carbon atoms and moreparticularly of l or 2 carbon atoms, and/or by halogen, particularlychlorine or bromine, with the total number of the substituents being atmost 3, preferably 2, or R is naphthyl, quinolyl, isoquinolyl, thenyl orfuryl, which is unsubstituted or substituted by lower alkyl or loweralkoxy, particularly of 1 to 4 carbon atoms or by chlorine or bromine;

R and R are hydrogen or lower alkyl, particularly of l to 4 carbonatoms, and more particularly of l or 2 carbon atoms;

R and R are different from one another andare lower alkyl, loweralkenyl, lower alkynyl, lower alkoxy(lower alkyl), particularly of up to4 carbon atoms in each moiety, or cyclohexyl, which may be substitutedby hydroxy; and

R is lower alkyl, particularly of 1 to 4 carbon atoms, and moreparticularly of l to 3 carbon atoms, or benzyl.

The new compounds may be prepared as follows:

a. a ylidene-B-ketocarboxylic acid ester of the general formulaz' isreacted'with'a ,B-ketoc-arboxylic acid ester of the general fonnula:

R COCl-l COOR lf 3'-nitrobenzylideneacetoacetic acid methyl ester andwith an amine of the general formula: and either N-methylaminocrotonicacid isopropyl ester R NH or acetoacetic acid isopropyl ester andmethylamine 2 5 are used as the starting materials, the course of thereor a salt thereof, if appropriate wlth intermediate lsolaaction ofProcess Variant (a) can be represented by the tron of the N-substitutedenammocarboxylic acid ester following equation:

3 N H COOCH H COOC (CH H o 3 coo'c|-| 2 l H H COOC V 3 a H H I w 3 c c H3 o HN CH I 3 C H 3 0f the general formula: If 3-nitrobenzaldehyde,acetoacetic acid ethyl ester .1 and N-methylaminocrotonic acid isopropylester are R T=CH COOR 2 used as the starting materials, the followingequation NHR illustrates Process Variant (b):

cn cocn cooc n 01 cHcoocH(cH 2 4 H o NHC H 3 2 C HO H H C OOC coocH(cH\N/ H C I C H 3 C H w 3 or The starting materials used to prepare thecomb. an aldehyde of the general formula pounds of the invention areknown or can readlly be RCHO produced by known methods.

The ylidene-B-ketocarboxylic acid esters are known is reacted with anenaminocarboxylic acid ester of the or can be produced by known methods(org. Reactions general formula: XV, 204 ff, (1967)).

As examples there may be mentioned:

RT=CHC0OR2 Ylidene-B-ketocarboxylic acid esters NHR!2-nitrobenzylideneacetoacetic acid methyl ester,

2'-nitrobenzylideneacetoacetic acid ethyl ester, and a B'ketocarboxylicacid ester of the general 3'-nitrobenzylideneacetoacetic acid ethylester, mula: 3'-nitrobenzylideneacetoacetic acid methyl ester,

8 4 3'-nitrobenzylideneacetoacetic acid isopropy ester, R COCH2COOR3-nitrobenzylideneacetoacetic acid allyl ester, in water or an inertorganic solvent; 3-nitrobenzylideneacetoacetic acid propargyl ester, inwhich R, R, R R, R and R are as defined above.3'-nitrobenzylideneacetoacetic acid ,B-methoxy-ethyl The two modes (a)and (b) described above of efester,

3'-nitrobenzylideneacetoacetic acid cyclohexyl ester,

fecting the process of the invention will hereinafter be I3-nitrobenzylidenepropionylacetic acid ethyl ester,

referred to as Process Variants (a) and (b).

3 -nitro-4 '-methoxybenzylideneacetoacetic acid methyl ester, 2'-nitro-4 '-methoxybenzylideneacetoacetic acid methyl ester,

2-cyan0-4'-methylbenzylideneacetoacetic acid ethyl ester,

4-methylmercaptobenzylideneacetoacetic acid ethyl ester,

2'-methylmercaptobenzylideneacetoacetic acid methyl ester,

2-sulphinylmethylbenzylideneacetoacetic acid isopropyl ester,

2-sulphonylmethylbenzylideneacetoacetic acid ethyl ester,

(1-naphthylmethylidene)-acetoacetic acid methyl ester,

2'-ethoxy-( l '-naphthylmethylidene)-acetoacetic acid ethyl ester,

5 -bromo-( l '-naphthylmethylidene)-acetoacetic acid methyl ester,

(2-quinolyl)-methylideneacetoacetic acid ethyl ester,

(8'-quinolyl)-methylideneacetoacetic acid methyl ester,

(l'-isoquinolyl)-methylideneacetoacetic acid ethyl ester,

(3'-isoquinolyl)-methylideneacetoacetic acid isopropyl ester,

a-pyridylmethylideneacetoacetic acid methyl ester,

a-pyridylmethylideneacetoacetic acid ethyl ester,

a-pyridylmethylideneacetoacetic acid cyclohexyl ester,

B-pyridylmethylideneactoacetic acid ,B-ethoxyethyl ester,

6-methyl-a-pyridylmethylideneacetoacetic acid ethyl ester,

4 ,6'-dimethoxy-( 5 -pyrimidyl)-methylideneacetoacetic acid ethyl ester,

(2-thenyl)-methylideneacetoacetic acid ethyl ester,

2-furfurylideneacetoacetic acid ethyl ester,

(2-pyrryl)-methylideneacetoacetic acid methyl ester andoz-pyridylmethylidene propionylacetic acidethyl ester.

The ,B-ketocarboxylic acid esters are known or can be produced by knownmethods (Pohl and Schmidt, US. Pat. No. 2,351,366 (1940), ref. inChemical Abstracts l944, 5224).

As examples there may be mentioned:

B-Ketocarboxylic acid esters Formylacetic acid ethyl ester,

acetoacetic acid methyl ester,

acetoacetic acid ethyl ester,

acetoacetic acid propyl ester,

acetoacetic acid isopropyl ester,

acetoacetic acid 6-butyl ester,

acetoacetic acid butyl ester,

acetoacetic acid (aor B-)methoxyethyl ester,

acetoacetic acid (aor B- )propoxyethyl ester, acetoacetic acid (aorB-)hydroxyethyl ester, acetoacetic ,acid ally] ester, acetoacetic acidpropargyl ester, acetoacetic acid cyclohexyl ester, propionylacetic acidethyl ester, butyrylaceticacid methyl ester, and. isobutyrylacetic acidethyl ester.

The amines'of general formula R Nl-I are known. As examples there may bementioned: methylamine, ethylamine, propylamine, isopropylamine,butylamine, isobutylamine and benzylarnine.

The N-substituted enaminocarboxylic acid esters are known or can beproduced by known methods (A.C. Cope, J.A.C.S. 67, 1017 (1945)).

As examples there may be mentioned:

N-Substituted enaminocarboxylic acid esters B-N-Methylaminocrotonic acidmethyl ester, B-N-methylaminocrotonic acid ethyl ester,B-N-methylaminocrotonic acid isopropyl ester, ,B-N-ethylaminocrotonicacid ethyl ester, B-N-isopropylaminocrotonic acid methyl ester,B-N-methylaminocrotonic acid B-methoxyethyl ester,B-N-methylaminocrotonic acid cyclohexyl ester,,B-N-methylamino-B-ethylacrylic acid ethyl ester andB-N-benzylaminocrotonic acid ethyl ester.

The aldehydes of general formula RCI-IO are known or can be produced byknown methods (E. Mosettig, Org. Reactions VIII, 218 ff. (1954)).

As examples there may be mentioned:

2-, 3- or 4-Nitrobenzaldehyde,

2,4- or 2,6-dinitrobenzaldehyde, 2-nitro-6-bromobenzaldehyde,2-nitro-3-methoxybenzaldehyde, 2-nitro-3-methoxy-6-chlorobenzaldehyde,2-nitro-4-methoxybenzaldehyde, 3-nitro-6-chlorobenzaldehyde,

2-, 3- or 4-cyanobenzaldehyde,

01-, ,B- or 'y-pyridinaldehyde. 6-methylpyridin-2-aldehyde,pyrimidin-S-alde'hyde, 4,6-dimethoxy-pyrimidin-5-aldehyde,2-methylmercaptobenzaldehyde, 2-methylsulphonylbenzaldehyde,2-methylsulphinylbenzaldehyde,

1- and 2-naphthaldehydes,

S-bromo- 1 -naphthaldehyde, 2-ethoxyl-naphthaldeh yde, 4-methyll-naphthaldeh yde, quinolin-2-, 3-, 4-, 5-, 6-, 7- and 8-aldehydes,isoquinolin-l and 3-aldehydes, furan-2-aldehyde, thiophen-2-aldehyde andpyrrol-2-aldehyde.

Possible solvents for use in the process of the invention are water andall inert organic solvents. Preferably, the solvents are alcohols, suchas ethanol and methanol, ethers, such as dioxane and diethyl ether,glacial acetic acid, dimethylformamide, dimethylsulphoxide, acetonitrileand pyridine.

The reaction temperatures can be varied within a substantial range. Ingeneral, the reaction is carried out at between 20 and 200C, preferablyat the boiling point of the solvent.

The reaction can be carried out under normal pressure but also atelevated pressure. In general, normal pressure is used.

In carrying out the process according to the invention, the substancesparticipating in the reaction are each employed in approximatelystoichiometric amounts, except that in Process Variant (a), the amine orits salt which is used is appropriately added in an excess of l to 2mols.

Typical compounds of the invention are: l-methyl- 4-( 2 '-nitrophenyl)-l ,4-dihydropyridine-3 ,5-

dicarboxylic acid 3-methyl-ester-5-isopropyl-ester.l,2,6-trimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3,S-dicarboxylicacid 3-methyl-ester-5- isopropyl-ester.

l ,2,6-trimethyl-4-( 3 -nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl-ester-5-ethylester.

1 ,2,6-trimethyl-4-( 3 '-nitrophenyl )-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl-ester-5-isopropylester.

1 ,2,6-trimethyl-4-( 3 '-nitrophenyl)-l,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl-ester-5-allyl-ester.

l ,2,6-trimethyl-4-( 3 -nitrophenyl)-l,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl-ester-5-B-methoxyethylester.

l-benzyl-2,6-dimethyl-4-( 3 '-nitrophenyl)-l,4-dihydropyridine-3,S-dicarboxylic acid 3-methyl-ester-5- ethyl-ester.

l ,2,6-trimethyl-4-( 3 '-nitrophenyl)- l ,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl-ester-5- cyclohexyl-ester.

l ,6-dimethyl-2-ethyl-4- 3 '-nitrophenyl)-1,4-dihydropyridine-3,S-dicarboxylic acid3-ethyl-ester-5-isopropyl-ester.

l ,2,6-trimethyl-4-( 2 '-cyanophenyl )-l,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl-ester-5-ethylester.

1 ,2,6-trimethyl-4-( 2 -cyanophenyl)-l,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl-ester-S-allyl-ester.

l ,2,6-trimethyl-4-(2 '-cyanophenyl)-l,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl-ester-5-isopropylester.

1 ,6-dimethyl-2-ethyl-4-( 2 '-cyanophenyl)-l,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl-ester-5- methyl-ester.

l-benzyl-2,6-dimethyl-4-( 2 -cyanophenyl)-l,4-dihydropyridine-3,S-dicarboxylic acid 3-methyl-ester-5- ethyl-ester.

l,2,6-trimethyl-4-( 3 -nitro-6'-chlorophenyl)-1,4-dihydropyridine-3,S-dicarboxylic acid3-ethyl-ester-5-isopropyl-ester.

l ,2,6-trimethyl-4-( 3 '-nitro-6'-chlorophenyl)-l,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl-ester-5-B-methoxyethylester.

1 ,2,6-trimethyl-4-(furyl-2 )-l ,4-dihydropyridine-3 ,5-

dicarboxylic acid 3-methyl-ester-S-ethyl-ester.

1-benzyl-2,6-dimethyl-4-(furyl-2 l ,4-dihydropyridine-3,5-dicarboxylicacid 3-methyl-ester-5-isopropyl-ester.

As noted above, the compounds of the present invention demonstrate theability to reduce blood pressure and to effect a dilation of thecoronary vessels. They can accordingly be used where either or both ofthese effects are desired. Thus upon parenteral, oral or sublingualadministration, the compounds produce a distinct and long lastingdilation of the coronary vessels which is intensified by a simultaneousnitrite-like effect of reducing the load on the heart. In their strengthof action, the compounds of the invention are superior to the knownsymmetrical N-substituted dihydropyridinedicarboxylic acid esters. Theeffect on heart metabolism is thus one of energy saving. In addition,the compounds lower the blood pressure of normotonic and hypertonicanimals and can thus be used as antihypertensive agents. Theseproperties can be conveniently observed in well known laboratory models.Thus, for example, the coronary vessel dilation effect of the compoundsof the invention was compared with the action of Persantin by measuringthe rise in oxygen saturation in the coronary sinus in the narcotized,heart-catheterized dog, with the results reported in Table 1, below.

Table I Compound Dose mg/ 0 Rise Reversion kg, time Example 2 0.01 313.5 Example 3 0.1 39 6 Example 6 0.05 39 4 Persantin 0.3 23 1-2 do. 0434 1-2 Notes Dose given in mg/kg. body weight. administeredintravenously;

*0, rise given as 7: rise in oxygen saturation;

"Reversion time given is time in hours for reversion to the initialvalue.

The hypotensive activity of the present compounds can be observed bymeasuring the blood pressure of hypertensive rats followingadministration of the compounds. Table II below demonstrates the lowestdose which results in at least a 15 mm Hg reduction in blood pressure ofsuch animals.

Table II Compound Peroral Dose Example 1 0.3 Example 2 1.0 Example 3 0.3Example 6 0.3

The toxicity of the present compounds is favorable, as demonstrated bythe data in Table III below, which reports the LD as measured on mice byperoral administration.

Table III Compound LD (mg/kg) Example 1 3000 Example 2 3000 Example 33000 tem. Finally, there is some evidence that the com-' poundsinfluence the cholesterol level and lipid level of the blood. Theseeffects complement one another and the compounds are thus highlydesirable as pharmaceutical agents to be used in the treatment ofhypertension and conditions characterized by a constriction of thecoronary blood vessels.

Phamiaceutical compositions for effecting such treatment will contain amajor or minor amount, eg from 0.1 to 99.5%, preferably from 0.5 to 90%,of at least one compound of the invention in combination with aphannaceutical carrier, the carrier comprising one or more solid,semi-solid or liquid diluent, filler and formulation adjuvant which; isI non-toxic, inert and pharmaceutically acceptable. Such pharmaceuticalcompositions are preferably in dosage unit form; i.e. physicallydiscrete units containing a predetermined amount of the drugcorresponding to a fraction or multiple of the dose which is calculatedto produce the desired therapeutic response. The dosage units cancontain one, two, three, four or more single doses or, alternatively,one-half, third or fourth of a single dose. A single dose preferablycontains an amount sufficient to produce the desired therapeutic effectupon adminstration at one application of one or more dosage unitsaccording to a predetermined dosage regimen, usually a whole, half,third or quarter of the daily dosage administered once, twice, three orfour times a day. Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case becarefullyadjusted, utilizing sound professional judgment and considering the.age, weight and condition of the recipient, the'route of administrationand the nature and gravity of the illness, generally the daily dose willbe from about 0.001 to about mg/kg, preferably 0.002 to 1 mg/kg, whenadministered parenterally, and from about 0.05 to about 50 mg/kg,preferably 0.5 to l0 mg/kg, wheniadministered orally. In some instancesa sufficient therapeutic effect can be obtained at lower doses while inothers, larger doses will be required. Administration is preferablyparenterally or perorally, and more preferably byintravenous orperlingual routes.

Oral administration can be effected utilizing solid and liquid dosageunit forms such aspowders, tablets, dragees, capsules, granulates,suspensions, solution, and the like.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical-carrier such as anedible carbohydrate as for example starch, lactose, sucrose, glucose ormannitol. Sweetening, flavoring, preservative, dispersing and coloringagents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally with a binder such as carboxymethyl cellulose, analginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption acceleration such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acacia mucilage or solutions of cellulosic orpolprotective coating consisting of a sealing coat of shellac, a coatingof sugar or polymeric material and a polish coating of wax can beprovided. Dyestuffs can be added 1 to these coatings to distinguishdifferent unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous sucrose solution while elixirsare prepared through the use of a non-toxic alcoholic vehicleSuspensions can be formulated by dispersing the compound in a non-toxicvehicle. Solubiliz- 'ers and emulsifiers such as ethoxylated isostearylalcohols and polyoxyethylene sorbitol esters," preservatives, flavoradditives such as peppermint oil or saccharin, and the like ,can also'beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolongorsustain the release as, for example, by coating or embeddingparticulate material in polymers, wax, or the like.

Parenteral administration can be effected utilizing liquid dosage unitforms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection.'Th ese areprepared by suspending or dissolving a measured amount of the compoundin a non-toxic liquid vehicle suitable for injection such as an aqueousor oleaginous medium and sterilizing the suspension or solution.Alternatively, a measured amount of the compound is placed in a vial andthe vial and its contents sterilized and sealed. An accompanying vial orvehicle can be provided for mixing prior to administration. Non-toxicsalts and salt solutions can be added to render the injectionisotonic.Stabilizers, preservatives and emulsifiers can also be added.

The followingExamples will serve to further typify the nature of thepresent invention through the presentation of specific embodiments.These Examples should not be construed as a limitation on the scope ofthe invention since the subject matter regarded as the invention is setforth in the appended claims.

EXAMPLE 1 I l 2, 6 -trimethyl-4-( 3 '-nitrophenyl)-l,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl-ester-5-ethyl-ester ofmelting point lOOC (ethyl acetate/petroleum ether) was obtained byboiling a solution of 24.9g of 3- nitrobenzylideneacetoacetic acidmethyl ester' and 143g of N-methylaminocrotonic acid ethyl ester in 150ml of glacial acetic acid for 8 hours.

Yield: 49% of theory.

I EXAMPLE 2 COOCH(CH3)2 After heating a solution of 24.9g of3'-nitrobenzylideneacetoacetic acid methyl ester, 144g of acetoaceticacid isopropyl ester and 7.0g of methylamine hydrochloride in 150 ml ofpyridine for 4 hours, 1,2,6- trimethyl-4-( 3 -nitrophenyl )-l,4-dihydropyridine-3 ,5- dicarboxylic acid3-methyl-ester-S-isopropyl-ester of melting point lO8l09C (from alcohol)was obtained. Yield: 59% of theory.

EXAMPLE 3 (PROCESS VARIANT B) ICOOCH(CH3) 2 l ,2,6-trimethyl-4-( 3'-nitrophenyl)-l ,4-dihydropyridine-3,5-dicarboxylic acid3-ethyl-ester-5-isopropylester of melting point 100-l01C (ethanol) wasobtained by boiling a solution of 7.6g of 3-nitrobenzaldehyde, 7.2g ofacetoacetic acid isopropyl ester and 7.2g of N-methylaminocrotonic acidethyl ester in 150 ml of ethanol/glacial acetic acid (2:3) for 6 hours.

Yield: 47% of theory.

After boiling a solution of 26.3g of 3-nitrobenzylideneacetoacetic acidethyl ester and 142g of aceto- 12 acetic acid allyl ester and 7.0g ofmethylamine hydrochloride in 200 ml of pyridine for 6 hours, 1,2,6-trimethyl-4-( 3 -nitrophenyl)-l ,4-dihydropyridine-3,5- dicarboxylicacid 3-ethyl-ester-S-allyl-ester of melting point 65C (ether/petroleumether) was obtained. Yield: 38% of theory.

EXAMPLE 5 H H c ooc coocH l N l H3C CH3 After boiling a solution of24.3g of 2'-cyanobenzylideneacetoacetic acid ethyl ester, 11.6g ofacetoacetic acid methyl ester and 7.0g of methylamine hydrochloride inml of pyridine for 4 hours, 1,2,6- trimethyl-4-( 2 '-cyanophenyl )-1,4-dihydropyridine-3,5- dicarboxylic acid 3-methyl-ester-5-ethyl-esterof melting point C (ethanol) was obtained. Yield: 61% of theory.

EXAMPLE 6 After boiling a solution of 12.2g of2'-cyanobenzylideneacetoacetic acid ethyl ester, 7.2g of acetoaceticacid'allyl ester and 4g of methylamine hydrochloride in 80 ml ofpyridine for 2 hours, 1,2,6-trimethyl-4- (2 '-cyanophenyl l,4-dihydropyridine-3 ,S-dicarboxylic acid 3-ethyl-ester-S-aIlyl-ester ofmelting point 103l04C (ethyl acetate/petroleum ether) was obtained.

Yield: 46% of theory.

EXAMPLE7 Cl H cooc H 3 cooc u l I 11 c11 1 ,2,6-trimethyl-4-(6'-chloro-3 -nitrophenyl)- l ,4-dihydropyridine-3,S-dicarboxylic acid3-ethyl-ester-5- methyl-ester of melting point 164C was obtained byheating a solution of 142g of 6'-chloro-3'-nitrobenzylideneacetoaceticacid methyl ester, 6.5g of acetoacetic acid ethyl ester and 4g ofmethylamine hydrochloride in 100 ml of pyridine for 4 hours. Yield: 57%of theory. I

EXAMPLE 8 EXAMPLE 9 EXAMPLE 1O After heating a solution of 24.9g3'-riitroben- 14 zylideneacet oaceticacid methyl ester, 1.30gacetoacetic acid ethyl ester and 15.0g benzylamine hydrochloride in '200ml pyridine for 6 hours, 1-benzyl-2,6- dimethyl- 4-( 3 '-nitr ophenyl)-l ,4-dihydropyridine-3,5-

dicarboxylic acid 3-methyl ester S-ethyl ester of melting point 107C(ether) was obtained. Yield: 62% of theory.

EXAMPLE ll After boiling a solution of 22.2g of (2'-thenylidene)acetoacetic acid ethyl ester, 11.6g acetoacetic acid methylester and 15.0g benzylamine hydrochloride in 150 ml pyridine for 6hours, l-benzyl-2,6- dimethyl-4-( 2 '-thenyl)- 1 ,4-dihydropyridine-3,S-dicarboxylic acid 3-methyl ester S-ethyl ester of melting point 113C(ether) were obtained.

Yield: 49% of theory.

What is claimed is:

l. The method of effecting coronary vessel dilation and a reduction inblood pressure in an animal in need thereof, which comprisesadministering thereto an effective amount of a compound of the generalformula:

in which R is mono-, dior trisubstituted phenyl, in which thesubstituents are selected from the group consisting of nitro, cyano,azido and S(O) -lower alkyl, wherein n 0, l or 2, lower alkyl, loweralkoxy and halogeno, the total number of said substituents 5 beingnotmore than 3 and at least one of said substituents being nitro, cyano,azido or S(O),,-lower alkyl, R and R independent of the other, ishydrogen or lower alkyl;

6 R and R are different from one another and are lower alkyl, loweralkenyl, lower alkynyl, lower alkoxy('lower alkyl) or lower cycloalkyl,unsubstituted or substituted by hydroxy; R Iis lower alkyl or benzyl, 65or a pharmaceutically acceptable acid addition salt thereof.

2. The method according to claim 1, in which is 'phenyl substituted byone or two nitro, cyano, azido or S(O)',,-lower alkyl, inwhich n is O or2 and said lower alkyl has 1 to 4 carbon atoms, lower alkyl of l to 4carbon atoms, lower alkoxy of l to 4 carbon atoms or halogeno, at leastone of said substituents being said nitro, cyano, azido or S(O),,-loweralkyl.

3. The method according to claim 1, in which R and R are independentlyhydrogen or lower alkyl of l to 4 carbon atoms.

4. The method according to claim 1, in which R and R are different fromone another and are lower alkyl of l to 4 carbon atoms, lower alkenyl of2 to 4 carbon atoms, lower alkynyl of 2 to 4'carbon atoms, loweralkoxy(lower alkyl) with l to 4 carbon atoms in said lower alkoxy andlower alkyl moieties or cyclohexyl, unsubstitutedor substituted byhydroxy.

5. The method according to claim 1, in which R is lower alkyl of l to 4carbon atoms or benzyl.

6. The method according to claim 1, in which R is nitrophenyl,halogeno-substituted nitrophenyl,

cyanophenyl, or halogeno-substituted cyanophenyl, said halogeno beingchlorine or bromino,

R and R are independently hydrogen or lower alkyl,

R and R are different from one another and are lower alkyl, loweralkenyl, lower alkynyl, lower alkoxy(lower alkyl) or lower cycloalkyl,unsubstituted or substituted by hydroxy, and

R is lower alkyl or benzyl.

7. The method according to claim 1, in which R is nitrophenyl,nitrophenyl substituted by one or two halogeno selected from the groupconsisting of chloro and bromo, or cyanophenyl, R and R areindependently hydrogen or lower alkyl, R and R are different from oneanother and are lower alkyl, lower alkenyl, lower alkoxy(lower alkyl) orcyclohexyl, and R is lower alkyl or benzyl.

8. The method according to claim 1, wherein said compound is1-methyl-4-(2'-nitrophenyl)-l ,4-dihydropyridine-3,S-dicarboxylic acid3-methyl-ester-5-isopropyl-ester.

9. The method according to claim 1, wherein said compound isl,2,6-trimethyl-4-( 2 'nitrophenyl)- 1 ,4-dihydropyridine-3,S-dicarboxylic acid 3-methyl-3-ester-S-isopropyl-ester.

10. The method according to claim 1, wherein said compound is 1,2,6-trimethyl-4-(3 '-nitrophenyl)-1,4- dihydropyridine-3,S-dicarboxylicacid 3-methyl-ester- S-ethyl-ester.

11. The method according to claim 1, wherein said compound isl,2,6-trimethyl-4-( 3 '-nitrophenyl 1 ,4-dihydropyridine-3,S-dicarboxylic acid 3-ethyl-ester-5- isopropyl-ester.

12. The method according to claim 1, wherein said compound isl,2,6-trimethyl-4-(3-nitrophenyl)-l,4- dihydropyridine-3,S-dicarboxylicacid 3-ethyl-ester-5- allyl-ester.

13. The method according to claim 1, wherein said compound is l,2,6-trimethyl-4-(3 -nitrophenyl)- l ,4-dihydropyridine-3,S-dicarboxylic acid 3-methyl-ester-S-B-methoxyethylester.

14. The method according to claim 1, wherein said compound isl-benzyl-2,6-dimethyl-4-( 3-nitrophenyl)-l,4-dihydropyridine-3,S-dicarboxylic acid 3-methyl-ester-S-ethyl-ester.

15. The method according to claim 1, wherein said compound isl,2,6-trimethyl-4-( 3 '-nitrophenyl -1 ,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl-ester-S-cyclohexyl-ester.

16. The method according to claim 1, wherein said compound is1,6-dimethyl-2-ethyl-4-( 3 '-nitrophenyl 16 1,4-dihydropyridine-3,S-dicarboxylic ester-S-isopropyl-ester.

17. The method according to claim 1, wherein said compound isl,2,6-trimethyl-4-(2-cyanophenyl)-l,4- dihydropyridine-3,S-dicarboxylicacid 3-methyl-ester- S-ethyl-ester.

18. The method according to claim 1, wherein said compound is 1,2,6-trimethyl-4-(2'-cyanophenyl)- l ,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl-ester-5- allyl-ester.

19. The method according to claim 1, wherein said compound isl,2,6-trimethyl-4-(2-cyanophenyl)-1,4- dihydropyridine-3,S-dicarboxylicacid 3-ethyl-ester-5- isopropyl-ester.

20. The method according to claim 1 wherein said compound isl,6-dimethyl-2-ethyl-4-(2 '-cyanophenyl)-l,4-dihydropyridine-3,S-dicarboxylic acid 3-ethylester-S-methyl-ester.

21. The method according to claim 1, wherein said compound isl-benzyl-2,6-dimethyl-4-( 2-cyanophenyl)-l,4-dihydropyridine-3,S-dicarboxylic acid 3-methyl-ester-S-ethyl-ester.

22. The method according to claim 1, wherein said compound is1,2,6-trimethyl-4-(3-nitro-6-chlorophenyl)-l,4-dihydropyridine-3,S-dicarboxylicacid 3- ethyl-ester-S-isopropyl-ester.

23. The method according to claim 1, wherein said compound isl,2,6-trimethyl-4-(3'-nitro-6'-chlorophenyl)-1,4-dihydropyridine-3,S-dicarboxylicacid 3- ethyl-ester-S-B-methoxyethyl-ester.

24. The method according to claim 1, wherein said compound isl,2,6-trimethyl-4-(3-nitrophenyl)-l,4- dihydropyridine-3,S-dicarboXyIicacid 3-methyl-ester- S-isopropyl-ester.

25. The method according to claim 1, wherein said compound isl,2,6-trimethyl-4-(6-chloro-3-nitrophenyl)-1,4-dihydropyridine-3,S-dicarboxylic acid 3-e'thyl-ester-S-methyl-ester.

26. A pharmaceutical composition for use in effecting coronary vesseldilation and a reduction in blood pressure, which comprises an effectiveamount of a compound of the general formula:

acid 3-ethylstituents being nitro, cyano, azido or S(O),,-lower I alk l,

R an ii R independent of the other, is hydrogen or lower alkyl;

R and R are different from one another and are lower alkyl, loweralkenyl, lower alkynyl, lower alkoxy(lower alkyl) or lower cycloalkyl,unsubstituted or substituted by hydroxy;

R is lower alkyl or benzyl, or a pharmaceutically acceptable acidaddition salt thereof and a pharmaceutical carrier.

27. The composition according to claim 26, in which R is phenylsubstituted by one or two nitro, cyano, azido or S(O),,-lower alkyl, inwhich n is O or 2 and said lower alkyl has 1 to 4 carbon atoms, loweralkyl of l to 4 carbon atoms, lower alkoxy of l to 4 carbon atoms orhalogeno, at least one of said substituents being said nitro, cyano,azido or S(O),,-lower alkyl.

28. The composition according to claim 26, in which R and R areindependently hydrogen or lower alkyl of l to 4 carbon atoms.

29. The composition according to claim 26, in which R and R aredifferent from one another and are lower alkyl of l to 4 carbon atoms,lower alkenyl of 2 to 4 carbon atoms, lower alkynyl of 2 to 4 carbonatoms, lower alkoxy(lower alkyl) with l to 4 carbon atoms in said loweralkoxy and lower alkyl moieties or cyclohexyl, unsubstituted orsubstituted by hydroxy.

30. The composition according to claim 26, in which R is lower alkyl ofl to 4 carbon atoms or benzyl.

31. The composition according to claim 26, in which R is nitrophenyl,halogeno-substituted nitrophenyl,

cyanophenyl, or halogeno-substituted cyanophenyl, said halogeno beingchlorino or bromino,

R and R are independently hydrogen or lower alkyl,

R and R are different from one another and are lower alkyl, loweralkenyl, lower alkynyl, lower alkoxy(lower alkyl) or lower cycloalkyl,unsubstituted or substituted by hydroxy, and

R is lower alkyl or benzyl.

32. The composition according to claim 26, in which R is nitrophenyl,nitrophenyl substituted by one or two halogeno selected from the groupconsisting of chloro and bromo, or cyanophenyl, R and R areindependently hydrogen or lower alkyl, R and R are difierent from oneanother and are lower alkyl, lower alkenyl, lower alkoxy(lower alkyl) orcyclohexyl, and R is lower alkyl or benzyl.

33. The composition according to claim 26, wherein said compound is1-methyl-4-(2'-nitrophenyl).-1,4- dihydropyridine-3,S-dicarboxylic acid3-methyl-ester- 5-isopropyl-ester.

34. The composition according to claim 26, wherein said compound isl,2,6-trimethyl-4-(2'-nitrophenyl)- l,4-dihydropyridine-3,S-dicarboxylicacid 3-methyl-3- ester-S-isopropyl-ester.

35. The composition according to claim 26, which is l ,2,6-trimethyl-4-(3 '-nitrophenyl)- l ,4-dihydropyridine-3,5-dicarboxylic acid3-methyl-ester-5-ethylester.

36. The composition according to claim 26, which is 1 ,2,6-trimethyl-4-(3 '-nitrophenyl)-l ,4-dihydropyridine-3,5-dicarboxylic acid3-ethyl-ester-5-isopropylester.

37. The composition according to claim 26, which is l ,2,6-trimethyl-4-(3 -nitrophenyl)-l ,4-dihydropyridine-3,5-dicarboxylic acid3-ethyl-ester-5-allyl-ester.

38. The composition according to claim 26, which is l,2,6-trimethyl-4-(3 '-nitrophenyl)- l ,4-dihydropyridine-3,5-dicarboxylic acid3-methyl-ester-S-B-methoxyethylester.

39. The composition according to claim 26, which is l-benzyl-2,6dimethyl-4-( 3 '-nitrophenyl )-l ,4-dihydropyridine-3,5-dicarboxylicacid 3-methyl-ester-5- ethyl-ester.

40. The composition according to claim 26, which is l,2,6-trimethyl-'4-(3 -nitrophenyl)-l ,4-dihydropyridine-3,5-dicarboxylic acid3-methyl-ester-5-cyclohexyl-ester.

41. The composition according to claim 26, which is l,6-dimethyl-2-ethyl-4- 3 '-nitrophenyl)- l,4-dihydropyridine-3,S-dicarboxylic acid3-ethyl-ester-5-isopropyl-ester.

42. The composition according to claim 26, which is l,2,6-trimethyl-4-(2 "cyanophenyl )-l ,4-dihydropyridine-3,5-dicarboxylic acid3-methyl-ester-5-ethylester.

- 43. The composition according to claim 26, which is l,2,6-trimethyl-4-( 2 '-cyanophenyl)-l,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl-ester-5-allyl-ester.

44. The composition according to claim 26, which is l ,2,6-trimethyl-4-(2 -cyanophenyl)-l ,4-dihydropyridine-3,5-dicarboxylic acid3-ethyl-ester-5-isopropylester.

45. The composition according to claim 26, which is l,6-dimethyl-2-ethyl-4-(2-cyanophenyl)-l,4-dihydropyridine-3,S-dicarboxylic acid 3-ethyl-ester-5- methyl-ester.

46. The composition according to claim 26, which isl-benzyl-2,6-dimethyl-4 2 -cyanophenyl )-l,4-dihydropyridine-3,S-dicarboxylic acid 3-methyl-ester-5- ethyl-ester.

47. The composition according to claim 26, which is 1,2,6-trimetl1yl-4-( 3 '-nitro-6 '-chlorophenyl)-l,4-dihydropyridine-3,S-dicarboxylic acid3-ethyl-ester-5-isopropyl-ester.

48. The composition according to claim 26, which is l,2,6-trimethyl-4-(3 '-nitro-6 '-chlorophenyl)-1,4-dihydropyridine-3,S-dicarboxylic acid3-ethyl-ester-5-B- methoxyethyl-ester.

49. The composition according to claim 26, which is l,2,6-trimethyl-4-(3 -nitrophenyl)- l ,4-dihydropyridine-3,5-dicarboxylic acid3-methyl-ester-S-isopropylester.

50. The composition according to claim 26, which is l ,2,6-trimethyl-4-(6-chloro-3 '-nitrophenyl)-l ,4-dihydropyridine-3,S-dicarboxylic acid3-ethyl-ester-5- methyl-ester.

1. THE METHOD OF EFFECTING CORONARY VESSEL DILATION AND A REDUCTION INBLOOD PRESSURE IN AN ANIMAL IN NEED THEREOF, WHICH COMPRISESADMINISTERING THERETO AN EFFECTIVE AMOUNT OF A COMPOUND OF THE GENERALFORMULA:
 2. The method according to claim 1, in whIch R is phenylsubstituted by one or two nitro, cyano, azido or S(O)n-lower alkyl, inwhich n is 0 or 2 and said lower alkyl has 1 to 4 carbon atoms, loweralkyl of 1 to 4 carbon atoms, lower alkoxy of 1 to 4 carbon atoms orhalogeno, at least one of said substituents being said nitro, cyano,azido or S(O)n-lower alkyl.
 3. The method according to claim 1, in whichR1 and R3 are independently hydrogen or lower alkyl of 1 to 4 carbonatoms.
 4. The method according to claim 1, in which R2 and R4 aredifferent from one another and are lower alkyl of 1 to 4 carbon atoms,lower alkenyl of 2 to 4 carbon atoms, lower alkynyl of 2 to 4 carbonatoms, lower alkoxy(lower alkyl) with 1 to 4 carbon atoms in said loweralkoxy and lower alkyl moieties or cyclohexyl, unsubstituted orsubstituted by hydroxy.
 5. The method according to claim 1, in which R5is lower alkyl of 1 to 4 carbon atoms or benzyl.
 6. The method accordingto claim 1, in which R is nitrophenyl, halogeno-substituted nitrophenyl,cyanophenyl, or halogeno-substituted cyanophenyl, said halogeno beingchlorino or bromino, R1 and R3 are independently hydrogen or loweralkyl, R2 and R4 are different from one another and are lower alkyl,lower alkenyl, lower alkynyl, lower alkoxy(lower alkyl) or lowercycloalkyl, unsubstituted or substituted by hydroxy, and R5 is loweralkyl or benzyl.
 7. The method according to claim 1, in which R isnitrophenyl, nitrophenyl substituted by one or two halogeno selectedfrom the group consisting of chloro and bromo, or cyanophenyl, R1 and R3are independently hydrogen or lower alkyl, R2 and R4 are different fromone another and are lower alkyl, lower alkenyl, lower alkoxy(loweralkyl) or cyclohexyl, and R5 is lower alkyl or benzyl.
 8. The methodaccording to claim 1, wherein said compound is1-methyl-4-(2''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid3-methyl-ester-5-isopropyl-ester.
 9. The method according to claim 1,wherein said compound is 1,2,6-trimethyl-4-(2''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-methyl-3-ester-5-isopropyl-ester.
 10. The method according toclaim 1, wherein said compound is 1,2,6-trimethyl-4-(3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-methyl-ester-5-ethyl-ester.
 11. The method according to claim 1,wherein said compound is 1,2,6-trimethyl-4-(3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl-ester-5-isopropyl-ester.
 12. The method according to claim1, wherein said compound is 1,2,6-trimethyl-4-(3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl-ester-5-allyl-ester.
 13. The method according to claim 1,wherein said compound is 1,2,6-trimethyl-4-(3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-methyl-ester-5- Beta -methoxyethylester.
 14. The method accordingto claim 1, wherein said compound is1-benzyl-2,6-dimethyl-4-(3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl-ester-5-ethyl-ester.
 15. The methodaccording to claim 1, wherein said compound is 1,2,6-trimethyl-4-(3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-methyl-ester-5-cyclohexyl-ester.
 16. The method according toclaim 1, wherein said compound is 1,6-dimethyl-2-ethyl-4-(3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl-ester-5-isopropyL-ester.
 17. The method according to claim1, wherein said compound is 1,2,6-trimethyl-4-(2''-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-methyl-ester-5-ethyl-ester.
 18. The method according to claim 1,wherein said compound is 1,2,6-trimethyl-4-(2''-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl-ester-5-allyl-ester.
 19. The method according to claim 1,wherein said compound is 1,2,6-trimethyl-4-(2''-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl-ester-5-isopropyl-ester.
 20. The method according to claim1 wherein said compound is 1,6-dimethyl-2-ethyl-4-(2''-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl-ester-5-methyl-ester.
 21. The method according to claim 1,wherein said compound is1-benzyl-2,6-dimethyl-4-(2''-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl-ester-5-ethyl-ester.
 22. The methodaccording to claim 1, wherein said compound is 1,2,6-trimethyl-4-(3''-nitro-6''-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl-ester-5-isopropyl-ester.
 23. The methodaccording to claim 1, wherein said compound is 1,2,6-trimethyl-4-(3''-nitro-6''-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl-ester-5- Beta -methoxyethyl-ester.
 24. Themethod according to claim 1, wherein said compound is 1,2,6-trimethyl-4-(3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-methyl-ester-5-isopropyl-ester.
 25. The method according to claim1, wherein said compound is 1,2,6-trimethyl-4-(6''-chloro-3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl-ester-5-methyl-ester.
 26. A PHARMACEUTICALCOMPOSITION FOR USE IN EFFECTING CORONARY VESSEL DILATION AND AREDUCTION IN BLOOD PRESSURE, WHICH COMPRISES AN EFFECTIVE AMOUNT OF ACOMPOUND OF THE GENERAL FORMULA:
 27. The composition according to claim26, in which R is phenyl substituted by one or two nitro, cyano, azidoor S(O)n-lower alkyl, in which n is 0 or 2 and said lower alkyl has 1 to4 carbon atoms, lower alkyl of 1 to 4 carbon atoms, lower alkoxy of 1 to4 carbon atoms or halogeno, at least one of said substituents being saidnitro, cyano, azido or S(O)n-lower alkyl.
 28. The composition accordingto claim 26, in which R1 and R3 are independently hydrogen or loweralkyl of 1 to 4 carbon atoms.
 29. The composition according to claim 26,in which R2 and R4 are different from one another and are lower alkyl of1 to 4 carbon atoms, lower alkenyl of 2 to 4 carbon atoms, lower alkynylof 2 to 4 carbon atoms, lower alkoxy(lower alkyl) with 1 to 4 carbonaToms in said lower alkoxy and lower alkyl moieties or cyclohexyl,unsubstituted or substituted by hydroxy.
 30. The composition accordingto claim 26, in which R5 is lower alkyl of 1 to 4 carbon atoms orbenzyl.
 31. The composition according to claim 26, in which R isnitrophenyl, halogeno-substituted nitrophenyl, cyanophenyl, orhalogeno-substituted cyanophenyl, said halogeno being chlorino orbromino, R1 and R3 are independently hydrogen or lower alkyl, R2 and R4are different from one another and are lower alkyl, lower alkenyl, loweralkynyl, lower alkoxy(lower alkyl) or lower cycloalkyl, unsubstituted orsubstituted by hydroxy, and R5 is lower alkyl or benzyl.
 32. Thecomposition according to claim 26, in which R is nitrophenyl,nitrophenyl substituted by one or two halogeno selected from the groupconsisting of chloro and bromo, or cyanophenyl, R1 and R3 areindependently hydrogen or lower alkyl, R2 and R4 are different from oneanother and are lower alkyl, lower alkenyl, lower alkoxy(lower alkyl) orcyclohexyl, and R5 is lower alkyl or benzyl.
 33. The compositionaccording to claim 26, wherein said compound is1-methyl-4-(2''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid3-methyl-ester-5-isopropyl-ester.
 34. The composition according to claim26, wherein said compound is1,2,6-trimethyl-4-(2''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-methyl-3-ester-5-isopropyl-ester.
 35. The composition accordingto claim 26, which is1,2,6-trimethyl-4-(3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-methyl-ester-5-ethyl-ester.
 36. The composition according toclaim 26, which is1,2,6-trimethyl-4-(3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl-ester-5-isopropyl-ester.
 37. The composition according toclaim 26, which is1,2,6-trimethyl-4-(3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl-ester-5-allyl-ester.
 38. The composition according to claim26, which is1,2,6-trimethyl-4-(3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-methyl-ester-5- Beta -methoxyethylester.
 39. The compositionaccording to claim 26, which is 1-benzyl-2,6-dimethyl-4-(3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid3-methyl-ester-5-ethyl-ester.
 40. The composition according to claim 26,which is1,2,6-trimethyl-4-(3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-methyl-ester-5-cyclohexyl-ester.
 41. The composition according toclaim 26, which is1,6-dimethyl-2-ethyl-4-(3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl-ester-5-isopropyl-ester.
 42. The composition according toclaim 26, which is1,2,6-trimethyl-4-(2''-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-methyl-ester-5-ethyl-ester.
 43. The composition according toclaim 26, which is1,2,6-trimethyl-4-(2''-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl-ester-5-allyl-ester.
 44. The composition according to claim26, which is1,2,6-trimethyl-4-(2''-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl-ester-5-isopropyl-ester.
 45. The composition according toclaim 26, which is1,6-dimethyl-2-ethyl-4-(2''-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl-ester-5-methyl-ester.
 46. The composition according toclaim 26, whicH is 1-benzyl-2,6-dimethyl-4-(2''-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid3-methyl-ester-5-ethyl-ester.
 47. The composition according to claim 26,which is1,2,6-trimethyl-4-(3''-nitro-6''-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl-ester-5-isopropyl-ester.
 48. The compositionaccording to claim 26, which is1,2,6-trimethyl-4-(3''-nitro-6''-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl-ester-5- Beta -methoxyethyl-ester.
 49. Thecomposition according to claim 26, which is1,2,6-trimethyl-4-(3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-methyl-ester-5-isopropyl-ester.
 50. The composition according toclaim 26, which is1,2,6-trimethyl-4-(6''-chloro-3''-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl-ester-5-methyl-ester.